PROJECT SUMMARY High blood pressure (hypertension; HT) continues at epidemic levels in the United States. Despite the growing arsenal of antihypertensive drugs available, the fraction of patients responding adequately to traditional drug therapy remains unacceptably low. There is now indisputable evidence that increased sympathetic nervous system activity (SNA) is a major in the pathogenesis of HT. Drugs that globally impair neurogenic cardiovascular regulation have limited utility due to a poor side-effect profile. Is it possible to reduce SNA in a more regionally selective way (using drugs or other methods) and still lower blood pressure? The exciting recent demonstration in human patients of long-term antihypertensive responses to a novel device- based method of selective renal denervation suggests the answer is yes. The overall goal of this project is to advance our understanding of changes in regional specific SNA in experimental HT with the goal of developing novel target specific therapies. We will address these issues using a genetic model of salt-sensitive HT - the Dahl-S (DS) rat. Our preliminary data suggests that both renal denervation (RDNX) and splanchnic denervation, via celiac ganglionectomy (CGX), in DS rats cause dramatic reductions in AP of a magnitude similar to that seen in humans after catheter based renal nerve ablation. Specific Aim 1 will establish whether the cardiovascular responses to renal denervation (RDNX) are due to ablation of renal efferent or afferent neurons. Specific Aim 2 will define the cardiovascular and sympathetic mechanisms that mediate the acute and sustained antihypertensive responses to RDNX and/or renal deafferentation. Specific Aim 3 will define the cardiovascular and sympathetic mechanisms that mediate the acute and sustained antihypertensive responses to splanchnic sympathectomy via CGX. The expected outcome of the project is to generate a detailed understanding of the mechanisms whereby targeted sympathetic ablation can be used to treat HT. The expected impact is to focus new research attention on SNA and its effect on long-term cardiovascular regulation, and to potentially lead to novel, well-tolerated, organ-specific sympathetic blockade therapies to treat HT and other cardiovascular diseases.